GO:1904046 negative regulation of vascular endothelial growth factor production: Signaling Control, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1904046 describes any biological process that stops, prevents, or reduces the production of vascular endothelial growth factor (VEGF).
• VEGF is a key regulator of angiogenesis, and its production is tightly controlled at transcriptional, post-transcriptional, and translational levels.
• Negative regulation of VEGF production is critical in diseases such as cancer, where excessive VEGF drives tumor angiogenesis and immune evasion.
• Key molecular players include VEGFR1 (FLT1), which can sequester VEGF and modulate its availability, and signaling pathways involving eNOS and nitric oxide.
• CRISPR-based models, including knockout, point mutation, and knock-in, enable precise dissection of genes that negatively regulate VEGF production.
• Understanding this process offers therapeutic opportunities, as targeting VEGF production pathways is a mainstay in oncology and other angiogenesis-related diseases.
Description
Vascular endothelial growth factor (VEGF) is a potent mitogen that promotes angiogenesis, vascular permeability, and endothelial cell survival. Its production is tightly regulated to maintain vascular homeostasis, and dysregulated VEGF production contributes to numerous pathological conditions, including cancer, inflammatory diseases, and ischemia. The Gene Ontology term GO:1904046, negative regulation of vascular endothelial growth factor production, encompasses any process that stops, prevents, or reduces the frequency, rate, or extent of VEGF production. This term is essential for annotating gene products that suppress VEGF synthesis or secretion, providing a framework to study anti-angiogenic mechanisms and therapeutic targets. Research into negative regulation of VEGF production has revealed multiple layers of control, from transcriptional repression to post-transcriptional modifications and receptor-mediated feedback. For example, VEGFR1 (Flt-1) acts as a decoy receptor that can sequester VEGF, thereby negatively regulating its bioavailability. Additionally, signaling pathways involving endothelial nitric oxide synthase (eNOS) and nitric oxide have been implicated in modulating VEGF production under conditions such as isoflurane-induced cardiac preconditioning. These findings underscore the importance of understanding how cells restrict VEGF production to prevent aberrant angiogenesis. In cancer, negative regulation of VEGF production is often subverted, leading to sustained angiogenesis and tumor progression. Recent studies using single-cell RNA sequencing have shown that VEGF signaling mediates responses to anti-angiogenic therapies combined with immunotherapy in non-small cell lung cancer. Moreover, negative regulation of CPSF6 has been found to suppress the Warburg effect and angiogenesis in liver cancer, highlighting the interplay between metabolic reprogramming and VEGF regulation. Thus, GO:1904046 provides a critical lens for investigating the molecular mechanisms that restrain VEGF production and for developing strategies to manipulate this process therapeutically.
negative regulation of vascular endothelial growth factor production At A Glance
| GO ID | GO:1904046 |
|---|---|
| GO term | negative regulation of vascular endothelial growth factor production |
| Ontology | biological_process |
| Synonym | down regulation of VEGF production; inhibition of VEGF production; negative regulation of VEGF production |
| Major function | Suppression of VEGF synthesis or secretion, thereby inhibiting angiogenesis and vascular permeability |
| Related terms | regulation of VEGF production (GO:1904045); negative regulation of angiogenesis (GO:0016525) |
| Aspect | Biological process |
| Definition source | QuickGO |
What Is GO:1904046?
GO:1904046, negative regulation of vascular endothelial growth factor production, is defined as any process that stops, prevents, or reduces the frequency, rate, or extent of vascular endothelial growth factor production. This biological process includes mechanisms that inhibit the synthesis, processing, or secretion of VEGF, a key pro-angiogenic factor. It is a child of negative regulation of gene expression and regulation of VEGF production, and it plays a central role in controlling angiogenesis under physiological and pathological conditions.
Why Is negative regulation of vascular endothelial growth factor production Important in Cell Biology?
Negative regulation of VEGF production is crucial for maintaining vascular quiescence and preventing pathological angiogenesis. In cancer, tumors often overproduce VEGF to sustain growth and metastasis, so understanding how this process is negatively regulated can reveal new therapeutic targets. In cardiovascular diseases, modulating VEGF production can influence outcomes after ischemia-reperfusion injury. Furthermore, this term helps annotate genes that act as brakes on VEGF, providing a foundation for drug discovery and CRISPR-based functional studies.
• Controls angiogenesis and vascular permeability in health and disease.
• Dysregulation leads to tumor angiogenesis and cancer progression.
• Involved in cardiovascular protection, such as isoflurane-induced preconditioning.
• VEGFR1 (Flt-1) acts as a negative regulator by sequestering VEGF.
• Provides targets for anti-angiogenic therapies in oncology.
• CRISPR screens can identify novel negative regulators of VEGF production.
• Relevant to inflammatory and immune responses modulated by VEGF.
• Plays a role in metabolic reprogramming and the Warburg effect in cancer.
• Helps understand primary atopic disorders with vascular involvement.
• Guides development of gene editing strategies to modulate VEGF levels.
What Happens During negative regulation of vascular endothelial growth factor production?
Transcriptional repression of VEGF gene expression
In simple terms: The cell reduces the reading of the VEGF gene into messenger RNA.
Negative regulation of VEGF production often begins with transcriptional repression. Transcription factors and co-repressors can bind to the VEGF promoter and inhibit RNA polymerase II recruitment, reducing VEGF mRNA levels. For example, microglial control of astrocytes in response to microbial metabolites involves transcriptional programs that can suppress pro-angiogenic factors. Additionally, negative regulation of CPSF6 in liver cancer suppresses the Warburg effect and angiogenesis, partly through downregulation of VEGF transcription.
Post-transcriptional regulation of VEGF mRNA
In simple terms: After the mRNA is made, its stability or translation is reduced.
VEGF mRNA contains regulatory elements in its 5' and 3' untranslated regions that are targets for microRNAs and RNA-binding proteins. These factors can promote mRNA degradation or inhibit translation, thereby negatively regulating VEGF production. For instance, the RNA-binding protein CPSF6 has been implicated in angiogenesis regulation, and its negative regulation suppresses VEGF expression. This layer of control allows rapid adjustments in VEGF output without new transcription.
Inhibition of VEGF secretion or bioavailability
In simple terms: Even if VEGF is made, it can be kept from reaching its targets.
VEGF can be sequestered by soluble decoy receptors such as soluble VEGFR1 (sFlt-1), which binds VEGF and prevents it from activating VEGFR2 on endothelial cells. This negative regulation of VEGF production extends to the level of bioavailability, effectively reducing the amount of active VEGF available to stimulate angiogenesis. Such mechanisms are important in conditions like preeclampsia and cancer, where sFlt-1 levels modulate VEGF signaling.
Feedback regulation via VEGFR1 signaling
In simple terms: VEGF signaling itself can trigger a brake on its own production.
VEGFR1 (Flt-1) is a receptor tyrosine kinase that can negatively regulate VEGF signaling. It exists in both membrane-bound and soluble forms; the soluble form acts as a decoy, while the membrane-bound form can modulate downstream pathways that suppress VEGF production. This feedback loop helps prevent excessive angiogenesis. Dysregulation of this feedback can lead to pathological conditions, as seen in cancer where VEGFR1 expression is often altered.
Role of nitric oxide and eNOS in VEGF regulation
In simple terms: Nitric oxide signaling can turn down VEGF production.
VEGF regulates endothelial nitric oxide synthase (eNOS) phosphorylation, and in turn, nitric oxide can influence VEGF production. In isoflurane cardiac preconditioning, VEGF regulation of eNOS phosphorylation is involved in protective effects, suggesting a negative feedback where increased NO may suppress VEGF production. This crosstalk highlights the integration of VEGF and NO signaling in vascular homeostasis.
Key Genes Involved in GO:1904046 negative regulation of vascular endothelial growth factor production
The following genes and proteins are key players in the negative regulation of VEGF production, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| VEGFA | Encodes VEGF; its production is the target of negative regulation | Central to angiogenesis; knockout models are lethal |
| FLT1 (VEGFR1) | Decoy receptor that sequesters VEGF; negative regulator of VEGF bioavailability | Soluble form (sFlt-1) is a biomarker in preeclampsia and cancer |
| KDR (VEGFR2) | Main signaling receptor for VEGF; its activation can feedback to regulate VEGF production | Target of anti-angiogenic drugs; point mutations affect binding |
| CPSF6 | RNA-binding protein; its negative regulation suppresses VEGF and angiogenesis | Potential therapeutic target in liver cancer |
| NOS3 (eNOS) | Produces nitric oxide; involved in VEGF signaling feedback | Modulates VEGF production in cardiac preconditioning |
| HIF1A | Transcription factor that induces VEGF under hypoxia; negative regulators oppose its activity | Knockout reduces VEGF; target for cancer therapy |
| EPAS1 (HIF2A) | Transcription factor that can regulate VEGF; context-dependent | Implicated in clear cell renal cell carcinoma |
| STAT3 | Transcription factor that can promote VEGF; negative regulators inhibit its activation | Involved in tumor angiogenesis and immune evasion |
| NFKB1 | Transcription factor that induces VEGF; negative regulators suppress its pathway | Links inflammation and angiogenesis |
| SP1 | Transcription factor that activates VEGF promoter; negative regulators compete | Modulates basal VEGF expression |
| EGR1 | Transcription factor that can repress VEGF under certain conditions | Context-dependent regulator |
| TP53 | Tumor suppressor that can repress VEGF transcription | Loss of p53 leads to increased VEGF and angiogenesis |
| PTEN | Phosphatase that inhibits PI3K/AKT pathway, indirectly reducing VEGF | Frequently mutated in cancers |
| VHL | E3 ubiquitin ligase that targets HIF1A for degradation, reducing VEGF | Loss causes von Hippel-Lindau disease and high VEGF |
| PHD1/2/3 (EGLN1/2/3) | Prolyl hydroxylases that mark HIF for degradation, lowering VEGF | Oxygen sensors; targets for anemia and ischemia |
| miR-200b | MicroRNA that targets VEGF mRNA for degradation | Tumor suppressor miRNA; downregulated in cancers |
| miR-126 | MicroRNA that can modulate VEGF signaling | Endothelial-specific; involved in vascular integrity |
| SIRT1 | Deacetylase that can repress VEGF transcription via HIF1A deacetylation | Metabolic regulator; target in aging and cancer |
How Is negative regulation of vascular endothelial growth factor production Regulated?
The negative regulation of VEGF production is controlled by multiple signaling pathways. The PI3K/AKT/mTOR pathway can enhance HIF1A activity and VEGF production, so negative regulators often inhibit this axis. Conversely, AMPK activation can suppress mTOR and reduce VEGF. Hypoxia-inducible factors (HIFs) are central; under normoxia, prolyl hydroxylases (PHDs) hydroxylate HIF1A, leading to VHL-mediated degradation and reduced VEGF. Inflammatory signals via NF-kB and STAT3 can increase VEGF, while negative regulators like SOCS proteins dampen these pathways. Additionally, microRNAs such as miR-200b and miR-126 fine-tune VEGF mRNA stability and translation. The interplay between these pathways determines net VEGF output and is often disrupted in disease.
negative regulation of vascular endothelial growth factor production and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| VEGFA | Cancer, diabetic retinopathy | Knockout or knock-in of hypoxia response elements |
| FLT1 (VEGFR1) | Preeclampsia, cancer | Point mutation in ligand-binding domain; soluble form overexpression |
| CPSF6 | Liver cancer | Knockout and overexpression in hepatoma cell lines |
| NOS3 (eNOS) | Cardiac preconditioning | Point mutation at phosphorylation sites; knockout mice |
| HIF1A | Cancer, ischemia | Knockout or point mutation to prevent degradation (VHL-binding site) |
Cancer and tumor angiogenesis
In many cancers, negative regulation of VEGF production is impaired, leading to excessive angiogenesis that supports tumor growth and metastasis. For example, in non-small cell lung cancer, VEGF signaling mediates the response to neoadjuvant anlotinib combined with PD-1 blockade therapy, highlighting the therapeutic importance of modulating VEGF production. In liver cancer, negative regulation of CPSF6 suppresses the Warburg effect and angiogenesis, partly by reducing VEGF, suggesting that CPSF6 could be a therapeutic target. Loss of tumor suppressors such as TP53 or PTEN can relieve repression of VEGF, further promoting angiogenesis.
Cardiovascular diseases
VEGF regulation is critical in cardiac preconditioning and ischemia-reperfusion injury. In isoflurane cardiac preconditioning, VEGF regulation of eNOS phosphorylation is involved in protective effects, indicating that fine-tuning VEGF production is beneficial. Excessive VEGF can contribute to vascular permeability and edema, while insufficient VEGF impairs collateral vessel formation. Thus, negative regulation of VEGF production must be balanced to maintain cardiac health.
Inflammatory and immune disorders
Microglial control of astrocytes in response to microbial metabolites involves modulation of VEGF and other factors, linking negative regulation of VEGF production to neuroinflammation. In primary atopic disorders, genomic sequencing has revealed mutations in genes that may affect VEGF regulation, though direct links require further study. Chronic inflammation often elevates VEGF, and negative regulators serve to limit pathological angiogenesis in these contexts.
Ocular and metabolic diseases
Diabetic retinopathy and age-related macular degeneration are characterized by excessive VEGF production. Negative regulators of VEGF are potential therapeutic targets. Additionally, metabolic reprogramming in cancer, such as the Warburg effect, is tied to VEGF regulation; CPSF6 negative regulation suppresses both, offering a dual therapeutic strategy. Understanding these links can guide development of CRISPR-based therapies to restore negative regulation.
From negative regulation of vascular endothelial growth factor production-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X negatively regulate VEGF production? | CRISPR knockout of gene X in endothelial or cancer cells, followed by VEGF ELISA |
| Does a specific point mutation in VEGFR1 affect its decoy function? | Point mutation knock-in of FLT1 in cell lines, measure VEGF bioavailability |
| Can overexpression of a negative regulator reduce tumor angiogenesis? | Overexpression of candidate gene in cancer cells, xenograft models |
| What is the role of a miRNA in VEGF repression? | Knockout of miRNA gene or overexpression, measure VEGF mRNA and protein |
| How does a SNP in the VEGF promoter affect its repression? | Knock-in of SNP using CRISPR, reporter assays |
| Can CRISPR activation of a negative regulator suppress VEGF in vivo? | dCas9-VP64 activation of endogenous gene in mouse models |
How to Study the negative regulation of vascular endothelial growth factor production Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout | Loss-of-function of candidate gene | Identify negative regulators of VEGF |
| Point mutation knock-in | Effect of specific amino acid change | Dissect VEGFR1 decoy function |
| RNA-seq | Global transcriptome changes | Find pathways co-regulated with VEGF |
| ELISA | VEGF protein concentration | Quantify VEGF production in conditioned media |
| Tube formation assay | Angiogenic capacity in vitro | Assess functional impact of VEGF regulation |
| ChIP-seq | Transcription factor binding to VEGF promoter | Identify repressors and activators |
| CRISPR library screen | Unbiased identification of regulators | Discover novel negative regulators of VEGF |
CRISPR knockout and point mutation
CRISPR/Cas9-mediated knockout is a powerful method to test whether a gene is required for negative regulation of VEGF production. By disrupting candidate genes, researchers can measure changes in VEGF mRNA and protein levels using qPCR and ELISA. Point mutations can be introduced to dissect specific domains or phosphorylation sites, as demonstrated by prime editing of VEGFR2 to attenuate angiogenesis in vitro. These approaches allow precise functional annotation of genes in the context of GO:1904046.
Transcriptomic and proteomic profiling
RNA sequencing (RNA-seq) can identify global changes in gene expression upon perturbation of negative regulators. Single-cell RNA-seq has been used to reveal that VEGF signaling mediates responses to therapy in non-small cell lung cancer. Proteomics can quantify VEGF secretion and post-translational modifications. These methods help uncover pathways that converge on VEGF production.
Imaging and functional assays
Angiogenesis can be assessed using endothelial tube formation assays, aortic ring assays, and in vivo models such as zebrafish or mouse retinal vascularization. Fluorescent reporters for VEGF promoter activity enable live imaging of transcriptional changes. These functional readouts complement molecular analyses to confirm the impact of negative regulators on VEGF production.
Bioinformatics and pathway analysis
Computational analysis of CRISPR screening data, such as MAGeCK, can identify genes that negatively regulate VEGF production. Integration with public datasets (e.g., GTEx, TCGA) reveals disease associations. Pathway enrichment tools like DAVID or GSEA can place hits into biological processes, including GO:1904046. Such bioinformatics approaches accelerate target discovery.
How CRISPR Can Be Used to Study GO:1904046 negative regulation of vascular endothelial growth factor production
Knockout
CRISPR knockout of candidate genes is used to determine whether they are necessary for negative regulation of VEGF production. For example, knocking out CPSF6 in liver cancer cells can increase VEGF and angiogenesis, confirming its role as a negative regulator. Knockout models are also valuable for validating hits from genome-wide screens.
Point Mutation
Point mutations can be introduced to study specific residues critical for negative regulation. Prime editing of VEGFR2 has been used to attenuate angiogenesis in vitro, demonstrating the power of precise editing. Similarly, mutations in the VEGFR1 ligand-binding domain can abolish its VEGF-sequestering ability, leading to increased VEGF bioavailability.
Knock-in
Knock-in of reporter genes or tags allows real-time monitoring of VEGF production. For instance, inserting a luciferase reporter downstream of the VEGF promoter enables high-throughput screening for negative regulators. Knock-in of disease-associated SNPs can reveal their impact on VEGF repression.
Overexpression
Overexpression of candidate negative regulators can suppress VEGF production and inhibit angiogenesis. This approach is useful for testing therapeutic potential. For example, overexpressing soluble VEGFR1 (sFlt-1) sequesters VEGF and reduces angiogenesis in models of cancer and preeclampsia.
How EDITGENE Supports negative regulation of vascular endothelial growth factor production Research
Researchers studying negative regulation of vascular endothelial growth factor production-related genes often need to determine whether a candidate gene is causally involved in suppressing VEGF synthesis or secretion. EDITGENE provides a comprehensive suite of CRISPR services to accelerate this discovery, from knockout to precise point mutations and library screens.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of vascular endothelial growth factor production research.
Frequently Asked Questions About negative regulation of vascular endothelial growth factor production
What is GO:1904046?
GO:1904046 is a Gene Ontology term for any biological process that stops, prevents, or reduces the production of vascular endothelial growth factor (VEGF).
What genes are involved in negative regulation of VEGF production?
Key genes include FLT1 (VEGFR1), CPSF6, NOS3 (eNOS), TP53, PTEN, VHL, and various microRNAs like miR-200b.
How is VEGF production negatively regulated?
It occurs through transcriptional repression, mRNA degradation, inhibition of translation, and sequestration of VEGF protein by decoy receptors like sFlt-1.
Why is negative regulation of VEGF important in cancer?
It prevents excessive angiogenesis that supports tumor growth; loss of this regulation leads to increased VEGF and poor prognosis.
What experimental models study negative regulation of VEGF production?
CRISPR knockout, point mutation knock-in, overexpression cell lines, and xenograft models are commonly used.
Can CRISPR be used to study VEGF regulation?
Yes, CRISPR knockout and prime editing enable precise manipulation of genes to test their role in VEGF production.
What diseases are linked to dysregulated VEGF production?
Cancer, cardiovascular diseases, inflammatory disorders, and ocular diseases like diabetic retinopathy.
How does VEGFR1 negatively regulate VEGF?
Soluble VEGFR1 (sFlt-1) binds VEGF and prevents it from activating VEGFR2, reducing angiogenesis.
What methods measure VEGF production?
ELISA, qPCR, RNA-seq, and reporter assays are standard for quantifying VEGF mRNA and protein.
What services does EDITGENE offer for VEGF research?
EDITGENE provides CRISPR knockout, point mutation, knock-in, overexpression, library screening, and bioinformatics services to study VEGF regulation.
Conclusion
GO:1904046, negative regulation of vascular endothelial growth factor production, is a critical biological process that maintains vascular homeostasis and prevents pathological angiogenesis. Dysregulation of this process contributes to cancer, cardiovascular diseases, and inflammatory conditions. Advances in CRISPR gene editing and functional genomics have enabled precise dissection of the genes and pathways involved, offering new therapeutic opportunities. Continued research into this term will enhance our understanding of angiogenesis control and facilitate the development of targeted interventions.
References
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- 4. Huang Z et al.. 2025. scRNA-seq reveals that VEGF signaling mediates the response to neoadjuvant anlotinib combined with PD-1 blockade therapy in non-small cell lung cancer.. J Transl Med 23(1):478 PMID: 40281576
- 5. Liu Y et al.. 2019. Vascular endothelial growth factor regulation of endothelial nitric oxide synthase phosphorylation is involved in isoflurane cardiac preconditioning.. Cardiovasc Res 115(1):168-178 PMID: 29931049
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- 7. Sim DY et al.. 2024. Negative Regulation of CPSF6 Suppresses the Warburg Effect and Angiogenesis Leading to Tumor Progression Via c-Myc Signaling Network: Potential Therapeutic Target for Liver Cancer Therapy.. Int J Biol Sci 20(9):3442-3460 PMID: 38993554
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